ABSTRACT Systemic autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus are characterized by polyclonal T cell activation driving the production of pathogenic class switched autoantibodies. The class switched, somatically mutated antibodies are generated from germinal center (GC) B cells. A subset of effector CD4 T cells, known as T follicular helper (Tfh) cells, has been shown to play an integral role in production of antibodies by GC B cells. The importance of Tfh cells in lupus pathogenesis is understood by the increased numbers of Tfh cells observed in lymphoid organs in murine lupus, and the presence of Tfh cells found circulating in the blood of human lupus patients. Tfh cell secreted cytokines and their soluble factors control the overall dynamics of the GC reaction. The unique roles that Tfh cells have in the GC reaction and the importance of this process in forming pathogenic autoantibodies links these cells to the pathogenesis of systemic autoimmunity. Tfh and GC B cells require the transcriptional regulator protein B-cell lymphoma 6 (BCL6) for their development and function. In mice, genetic deletion of BCL6 abolishes Tfh and GC B cell development with a corresponding ablation of the germinal center response. A previously developed small molecule BCL6 inhibitor administered during a primary immunization in mice has shown the ability to inhibit GC B cell development. The initial focus of our study will be to utilize novel small molecule BCL6 inhibitors to inhibit Tfh and GC B cell responses (Aim 1) and ameliorate disease pathology in murine lupus (Aim 2). We will analyze Tfh and GC B cells in treated and control mice using flow cytometry and confocal microscopy. We will examine the generation of autoantibodies by ELISAs and assess kidney disease with H&E staining, and measure proteinuria after the treatment with our inhibitors. We will also examine efficacy of our new inhibitors compared to other newly developed BCL6 inhibitors. BCL6 regulation is essential for the generation and function of Tfh and GC B cells in lupus. Thus, we plan to validate our small molecule inhibitors of BCL6 as potential pharmacological agents for lupus. A successful Phase I project will reveal new and effective lupus therapeutic strategies and provide novel BCL6 inhibitors for Phase II medicinal chemistry to optimize efficacy and drug-like properties. The long-term project goal is to develop a novel targeted therapy to significantly improve treatment of lupus patients.